Safety and Effectiveness of Nabiximols Oromucosal Spray as Add-on Therapy in Participants With Spasticity Due to Multiple Sclerosis

A Double-blind, Randomized, Placebo-controlled, Parallel-group Trial of the Efficacy and Safety of Nabiximols Oromucosal Spray as Add-on Therapy in Patients With Spasticity Due to Multiple Sclerosis

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04203498

Acronym

RELEASE MSS3

Enrollment

139

Registered

2019-12-18

Start date

2020-10-01

Completion date

2023-02-28

Last updated

2024-05-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Sclerosis (MS)

Keywords

Spasticity

Brief summary

This trial is being conducted to demonstrate the efficacy of nabiximols, compared with placebo, when added to standard of care, in the treatment of muscle spasms associated with multiple sclerosis (MS).

Detailed description

This multicenter, double-blind, placebo-controlled trial includes a 28-day Baseline period, a 12-week treatment period (comprising a 2-week titration phase and a 10-week maintenance phase), and 2-week follow-up period. Eligible participants will enter the 28-day baseline period. During baseline, participants will maintain their optimized oral MS antispasticity medication regimen and record spasm count using an electronic daily diary. At screening (Day 1), eligible participants will be randomized to either nabiximols or placebo in a 1:1 ratio. Participants will be advised to titrate the investigational medicinal product (IMP), beginning with 1 spray/day, to an optimized dose or to a maximum of 12 sprays/day over the first 14 days of treatment. Participants may leave a gap between sprays of approximately 15 minutes. Participants should continue at the same dose level achieved at the end of the titration phase ±1 spray divided into a morning dose and an evening dose for the remainder of the treatment period. Daily spasm count, the participant's symptom experiences, clinician's assessment of spasticity, functional outcomes, health-related quality of life, changes in mood, safety, tolerability, and pharmacokinetics will be evaluated during the treatment period. Participants who complete the trial will participate for a total of approximately 18 weeks (127 days), including the 28-day baseline period. Participants will have a maximum duration of 85 (±7) days on IMP treatment.

Interventions

DRUGNabiximols

Nabiximols is a complex botanical medicine formulated from extracts of the cannabis plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) and also contains minor constituents, including other cannabinoid and non-cannabinoid plant components, such as terpenes, sterols, and triglycerides.Nabiximols will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks.

DRUGPlacebo

Placebo to match nabiximols will be presented as an oromucosal spray containing the excipients ethanol and propylene glycol (50% v/v) with colorings and flavored with peppermint oil (0.05% v/v). Each spray will deliver 100 microliters (μL) containing no active ingredients. Placebo will be self-administered by participants as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Criteria at screening: 1. Participant is male or female aged 18 years or above. 2. Participant has had a diagnosis with any disease subtype of multiple sclerosis (MS), by revised 2017 McDonald criteria, for at least 12 months prior to screening and is expected to remain stable for the duration of the trial. 3. Participant has had treatment with at least 1 optimized oral antispasticity therapy prior to Visit 1 that must include either oral baclofen or oral tizanidine (monotherapy or combination therapy). 4. Participant is currently receiving optimized treatment with at least 1 oral antispasticity medication (baclofen, tizanidine, and/or dantrolene) and has been stable for at least 30 days prior to screening. 5. If the participant is currently receiving an approved MS disease-modifying therapy, it must be at a stable dose for at least 3 months prior to screening and is expected to remain stable for the duration of the trial.

Exclusion criteria

1. Participant has any concomitant disease or disorder that has spasticity-like symptoms or that may influence the participant's level of spasticity. 2. Participant has had a relapse of MS within the 60 days prior to screening (Visit 1). 3. Participant is currently using or has used cannabis or a cannabinoid-derived product for medicinal or recreational use (within 30 days of screening) and is unwilling to abstain for the duration of the trial. 4. Participant is currently using botulinum toxin injection for the relief of spasticity (within 6 months of screening) and is unwilling to abstain for the duration of the trial. 5. Participant has any known or suspected hypersensitivity to cannabinoids or any of the excipients of the IMP. 6. Participant is male and fertile unless willing to ensure that he uses male contraception or remains sexually abstinent during the trial and for 3 months thereafter. 7. Participant is female and of childbearing potential unless willing to ensure that she uses a highly effective method of birth control during the trial and for 3 months thereafter. 8. Participant is female and pregnant, lactating, or planning pregnancy during the course of the trial or within 3 months thereafter. 9. Participant has received an IMP within the 30 days prior to screening. 10. Participant has a history of severe psychiatric disorder that may be exacerbated by the use of a cannabinoid-containing product. 11. Participant has any known or suspected history of alcohol or substance abuse (including opiate abuse) or dependence within 1 year prior to screening. 12. Participant is currently taking drugs that are solely metabolized by UGT1A9 and UGT2B7. 13. Participant is currently taking strong currently taking strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, St John's Wort).

Design outcomes

Primary

Measure	Time frame	Description
Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Baseline to Week 12	The change in the average daily spasm count was assessed compared to the baseline period.

Secondary

Measure	Time frame	Description
Number of Patients Reporting Any Treatment-emergent Adverse Events	From date of first dose of IMP up to 30 days after last dose, up to approximately 16 weeks	A TEAE is an adverse event that started, or worsened in severity or seriousness, following the first dose of the investigational medicinal product.
Change From Baseline in Clinical Laboratory Test Values	Baseline up to Week 12	—
Change From Baseline in Erythrocytes	Baseline up to Week 12	—
Change From Baseline in Hemoglobin	Baseline up to Week 12	—
Change From Baseline in Hematocrit Ratio	Baseline up to Week 12	The hematocrit ratio measures the volume of red blood cells compared to the total blood volume.
Change From Baseline in Erythrocyte Mean Corpuscular Hemoglobin	Baseline up to Week 12	—
Change in Multiple Sclerosis Spasticity Scale (MSSS-88) Total Score	Week 8 and Week 12	The MSSS-88 is a self-reported measure of the impact of spasticity (muscle stiffness and spasms) in MS. This 88-item scale captures the patient experience and impact of spasticity, including muscle stiffness, pain and discomfort, muscle spasms, effect on daily activities, ability to walk, body movement, patient feelings, and social functioning. Responses to individual questions can range from 1 - not at all bothered to 4 - extremely bothered, ranging from 88 to 352 total score. Scores are summed and higher scores indicate poor clinical outcome. Least square means are being reported, with greater negative values indicating better outcome.
Change From Baseline in Heart Rate	Baseline up to Week 12	—
Change From Baseline in Electrocardiogram Parameters	Baseline up to Week 12	—
Change From Baseline in Electrocardiogram Pulse Rate	Baseline up to Week 12	—
Change From Baseline in Weight	Baseline up to Week 12	—
Change in Body Mass Index	Baseline up to Week 12	—
Number of Patients With Suicidal Ideation or Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS)	Screening up to Week 12	The C-SSRS is a short questionnaire that is used to assess suicidal ideation (5 questions) and behavior (5 questions) since last patient visit. The questionnaire is completed by participants answering yes or no to each question.
Change From Baseline in Blood Pressure	Baseline up to Week 12	—

Countries

Czechia, Poland, Romania, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Nabiximols Patients randomized to receive GW-1000-2 (nabiximols) self-administered as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks.	67
Placebo Patients randomized to receive placebo self-administered as an oromucosal spray in the morning and evening, up to a maximum of 12 sprays per day for 12 weeks.	70
Total	137

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	4	1
Overall Study	Decision by the investigator, GW, or authority	0	1
Overall Study	Did not receive IMP	2	0
Overall Study	Drug not dispensed due to endpoint error	1	0
Overall Study	Withdrawal of patient consent	7	2

Baseline characteristics

Characteristic	Nabiximols	Placebo	Total
Age, Continuous	52.1 years STANDARD_DEVIATION 10.4	53.0 years STANDARD_DEVIATION 10.2	52.6 years STANDARD_DEVIATION 10.2
Age, Customized <18 years	0 Participants	0 Participants	0 Participants
Age, Customized ≥18 years to <45 years	14 Participants	15 Participants	29 Participants
Age, Customized ≥45 years to <65 years	44 Participants	46 Participants	90 Participants
Age, Customized ≥65 years	9 Participants	9 Participants	18 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Black or African American	3 Participants	1 Participants	4 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	2 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized White	62 Participants	68 Participants	130 Participants
Sex: Female, Male Female	43 Participants	52 Participants	95 Participants
Sex: Female, Male Male	24 Participants	18 Participants	42 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 67	0 / 70
other Total, other adverse events	46 / 67	19 / 70
serious Total, serious adverse events	3 / 67	5 / 70

Outcome results

Primary

Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period

The change in the average daily spasm count was assessed compared to the baseline period.

Time frame: Baseline to Week 12

Population: Average daily spasm count was assessed in participants with available data in the Full Analysis Set defined as all patients from the Safety Analysis Set who signed the informed consent and are randomized by interactive response technology..

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Nabiximols	Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Week 1 to 4	-2.23 daily spasm count	Standard Error 0.412
Nabiximols	Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Week 5 to 8	-3.42 daily spasm count	Standard Error 0.607
Nabiximols	Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Week 9 to 12	-3.84 daily spasm count	Standard Error 0.689
Placebo	Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Week 1 to 4	-1.62 daily spasm count	Standard Error 0.394
Placebo	Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Week 5 to 8	-2.62 daily spasm count	Standard Error 0.583
Placebo	Change in Average Daily Spasm Count From Baseline to Week 12 By 4-Week Period During the 12-Week Randomized Period	Week 9 to 12	-3.11 daily spasm count	Standard Error 0.659

Comparison: Week 9 to 12 (primary outcome statistics)p-value: =0.426395% CI: [-2.54, 1.08]Linear mixed model repeated measures

Secondary